Huntington's disease (HD) is a fatal inherited disorder with selective loss of neurons in the striatum. Disease can affect young and old alike, although symptoms usually being in mid-life. There is no effective treatment for HD. Our long-term goal is to understand the biochemical cause of HD, providing a fundamental basis for a rational therapy. HD is triggered by an expanded amino terminal polyglutamine tract in huntingtin, with formation of nuclear inclusions and amyloid. Precise genetic HD mouse model indicate early full-length, mutant protein in the nucleus of striatal target neurons. Our goal in this renewal is to identify early steps in a mutant protein in the nucleus of striatal target neurons. Our goal in this renewal is to identify early steps in a biochemical HD pathways that may involve a change in huntingtin's activity or that of an essential cellular protein. Criteria of the pathogenic property, dominance, glutamine progressivity and specificity will be used to judge if any of 13 binding proteins are qualified. Mutant huntingtin's impact on a functional feature of qualified partners will be assessed in in vitro, cellular and in vivo assays. WW domain proteins that implicate spliceosome function will be tested. A specific version of huntingtin, a modification or discrete complex, in striatal neurons will be sought. Finally, we will establish whether nuclear mutant huntingtin changes a specific pattern of gene transcription in striatal neurons by comparative identification of differentially expressed genes. Identification of a set of genes with common features may define a biochemical pathway that propagates the ultimately fatal cascade. These studies will yield rigorously evaluated candidate proteins and cellular processes likely to be involved in the initiation of HD pathogenesis. Each HD pathogenic intermediate provides an entry point for development. Each HD pathogenic interm3ediates provides an entry point for development of treatment paradigms that can be tested in vitro, cell and animal models, spurring progress toward an effective intervention for this tragic disorder.